Discovery of Genes Related to Diabetic Nephropathy in Various Animal Models by Current Techniques

Abstract

One of the major problems facing clinical nephrology currently throughout the world is an exponential increase in patients with end-stage renal disease (ESRD), which is largely related to a high incidence of diabetic nephropathy. The latter is characterized by a multitude of metabolic and signaling events following excessive channeling of glucose, which leads to an increased synthesis of extracellular matrix (ECM) glycoproteins resulting in glomerulosclerosis, interstitial fibrosis and ultimately ESRD. With the incidence of nephropathy at pandemic levels and a high rate of ESRD, physicians around the world must treat a disproportionately large number of diabetic patients with up-to-date innovative measures. In this regard, identification of genes that are crucially involved in the progression of diabetic nephropathy would enhance the discovery of new biomarkers and could also promote the development of novel therapeutic strategies. Over the last decade, we focused on the recent methodologies of high-throughput and genome-wide screening for identification of relevant genes in various animal models, which included the following: (1) single nucleotide polymorphism-based genome-wide screening; (2) the transcriptome approach, such as differential display reverse transcription polymerase chain reaction (DDRT-PCR), representational difference analysis of cDNA (cDNA-RDA)/suppressive subtractive hybridization, SAGE (serial analysis of gene expression) and DNA Microarray; and (3) the proteomic approach and 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) coupled with mass spectroscopic analysis. Several genes, such as Tim44 (translocase of inner mitochondrial membrane-44), RSOR/MIOX (renal specific oxidoreductase/myo-inositol oxygenase), UbA52, Rap1b (Ras-related GTPase), gremlin, osteopontin, hydroxysteroid dehydrogenase-3β isotype 4 and those of the Wnt signaling pathway, were identified as differentially expressed genes in kidneys of diabetic rodents. Functional analysis of these genes and the subsequent translational research in the clinical settings would be very valuable in the prevention and treatment of diabetic nephropathy. Future trends for identification of the biomarkers and therapeutic target genes should also include genome scale DNA/histone-methylation profiling, metabolomic approaches (e.g. metabolic phenotyping by 1H spectroscopy) and lectin microarray for glycan profiling along with the development of robust data-mining strategies.

Contribution of TGF-β1 and Effects of Gene Silencer Pyrrole-Imidazole Polyamides Targeting TGF-β1 in Diabetic Nephropathy

“…MCs in a normal glomerulus show the contractile phenotype, which do not proliferate, whereas MCs in an abnormal glomerulus by diabetes mellitus or hypertension shows the synthetic phenotype, inducing hyperproliferation with increases in organelles to produce many cytokines [21]. Increases in osteopontin, one of the synthetic phenotype markers and an inflammatory cytokine, strongly correlate with urinary albumin excretion and glomerulosclerosis in diabetic nephropathy [22]. The increased TGF-β1 contributes to the formation of glomerular ECM and albuminemia, seen with podocyte injury.…”

Tubular overexpression of Gremlin in transgenic mice aggravates renal damage in diabetic nephropathy

“…Gremlin was identified as one of the developmental genes induced in cultured human mesangial cells exposed to high glucose (24), and it is differentially expressed in kidneys of diabetic rodents (47) and in patients with diabetic nephropathy (10,23). Gremlin is a secreted member of the cysteine knot superfamily, belongs to a family of bone morphogenetic proteins (BMPs) antagonists, and is highly conserved during evolution (25,45).…”

Gremlin aggravates hyperglycemia‐induced podocyte injury by a TGFβ/smad dependent signaling pathway

“…G remlin is a developmental gene and is associated with dibetic nephropathy (DN) [Lappin et al, 2000]. It contains potential nuclear localization sites near its carboxyl-terminus, N-linked glycosylation sites, and a number of phosphorylation sites [Wada et al, 2011]. Gremlin is also a 23-28 kDa secreted protein, which is present as both soluble and cell-associated forms and is found within the Golgi apparatus and endoplasmic reticulum [Smerdel-Ramoya et al, 2011].…”